Humans are exposed to a variety of poorly virulent
micro-organisms. Only a minority of infected individuals
develop clinical disease. The interindividual variability of
clinical outcome is thought to result in part from variability
in the human genes that control host defense. In this
well-defined microbiological and clinical context, the
principles of mouse immunology and the methods of human
genetics can be combined to facilitate the genetic dissection
of immunity to infection in humans. The natural infections are
unique to the human model, not being found in any of the animal
models of experimental infection. We will review current
genetic knowledge concerning the simple and complex inheritance
of predisposition to infectious diseases in humans. Rare
patients with Mendelian disorders have been found to be
vulnerable to environmental microbes. Most cases of presumed
Mendelian susceptibility to these remain unexplained. In the
general population, common infectious diseases have been shown
to be associated with certain human genetic polymorphisms and
linked to certain chromosomal regions. However, the causal
vulnerability genes themselves have yet to be identified and
their pathogenic alleles biologically validated. The studies
carried out to date have been fruitful, initiating the genetic
dissection of protective immunity against a variety of
microbial species in natural conditions of infection. The human
model may well become a model of choice for the investigation
of immunity to infectious agents.